Rnf20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α [H3K4me3_ChIP]

Defective DNA repair and metabolic rewiring are highly intertwined in promoting the development and progression of cancer. However, the molecular players at the interface of these processes remain largely unexplored. Here we show that the Rnf20-HIF1α axis links the DNA damage response and metabolic reprogramming in lung cancer. Haploinsufficiency of Rnf20 which catalyzes monoubiquitylation of histone H2B (H2Bub1), dramatically increased the incidence of spontaneous lung adenocarcinoma and small cell lung cancer (SCLC) in mice. Mechanistically, ablation of a single Rnf20 allele resulted in inadequate tumor suppression via the Rnf20-H2Bub1-p53 axis and induced DNA damage, increased cell growth, epithelial-mesenchymal transition (EMT), and metabolic rewiring through HIF1α-mediated RNA polymerase II promoter-proximal pause release, that was independent of H2Bub1. Importantly, RNF20 levels are reduced in lung adenocarcinoma and SCLC patients, and this reduction negatively correlates with the expression of HIF1α target genes, suggesting HIF1α inhibition as a promising therapeutic approach for lung cancer patients with reduced RNF20 activity